Melanocortin peptides or melanotropins, α-MSH, β-MSH, γ-MSH and ACTH, are involved in many physiological functions in vertebrates, mammals and in man. They regulate skin pigmentation and steroid production, modulate immune responses and learning processes, influence energy balance, growth and regeneration of nerves, and several other functions as well.
Five human receptors are known which interact with melanotropins, hMC-1R to hMC-5R. The receptors are seven-helix transmembrane-spanning receptors and belong to the superfamily of G protein-coupled receptors; their activation leads to elevation of cAMP. The melanocortin receptors 1, 3, 4 and 5 recognize α-MSH, β-MSH and γ-MSH, while melanocortin receptor 2 recognizes only ACTH.
Considerable attention has recently focused on melanocortin receptors 3 and 4 that are widely expressed in the central nervous system, and also on melanocortin receptor 5, found in the brain and in various peripheral tissues. The physiological role of hMC-3R and hMC-5R is not well defined, although hMC-5R has recently been implicated in control of lipid and pheromone production in exocrine glands. Rapidly growing pharmacological and genetic evidence suggests that hMC-4R is involved in regulation of the energy balance and body weight in rodents. The role of MC-4R in regulation of food intake and body weight is supported by results obtained from agonist/antagonist administration in rats and from murine genetics. Intraventricular administration of the agonist MTII reduced food intake and conversely, the antagonist SHU9119 increased food intake and body weight. Mice genetically deficient in the melanocortin receptor 4 develop obesity. It could be anticipated therefore that compounds active at MC-4R might be useful in the treatment of eating disorders.
Melanocortin receptor 4 appears to play a role in other physiological functions as well, namely in controlling grooming behavior, erection and blood pressure. The natural hormones, melanotropins, however, have relatively low affinity for hMC3-5R and are not particularly selective. In order to differentiate the physiological role of melanocortin receptor 4 from that of other melanocortin receptors in the brain, in particular from MC-3R, potent and selective antagonists are necessary. The synthetic ligands available at present do not distinguish between the melanocortin receptors. A frequently used research tool is the SHU9119 peptide, a potent antagonist at melanocortin receptors 3 and 4, and an agonist at melanocortin receptor 5. SHU9119 has been extensively studied in vitro and in vivo; injection of this peptide stimulates food intake in rats. A similar lactam derivative, the peptide MTII is a potent but non-selective agonist at hMC3-5R.